title: Can BACE1 inhibition mitigate early axonal pathology in neurological diseases?
abstract: β-Secretase-1 (BACE1) is the rate-limiting enzyme for the genesis of amyloid-β (Aβ) peptides, the main constituents of the amyloid plaques in the brains of Alzheimer's disease (AD) patients. BACE1 is being evaluated as an anti-Aβ target for AD therapy. Recent studies indicate that BACE1 elevation is associated with axonal and presynaptic pathology during plaque development. Evidence also points to a biological role for BACE1 in axonal outgrowth and synapse formation during development. Axonal, including presynaptic, pathology exists in AD as well as many other neurological disorders such as Parkinson's disease, epilepsy, stroke, and trauma. In this review, we discuss pharmaceutical BACE1 inhibition as a therapeutic option for axonal pathogenesis, in addition to amyloid pathology. We first introduce the amyloidogenic processing of amyloid-β protein precursor and describe the normal expression pattern of the amyloidogenic proteins in the brain, with an emphasis on BACE1. We then address BACE1 elevation relative to amyloid plaque development, followed by updating recent understanding of a neurotrophic role of BACE1 in axon and synapse development. We further elaborate the occurrence of axonal pathology in some other neurological conditions. Finally, we propose pharmacological inhibition of excessive BACE1 activity as an option to mitigate early axonal pathology occurring in AD and other neurological disorders.
authors.affiliation: Department of Anatomy and Neurobiology, Central South University Xiangya School of Medicine, Changsha, Hunan, China.
authors.forename: Xiao-Xin
authors.initials: XX
authors.lastname: Yan
authors.forename: Chao
authors.initials: C
authors.lastname: Ma
authors.forename: Wei-Ping
authors.initials: WP
authors.lastname: Gai
authors.forename: Huaibin
authors.initials: H
authors.lastname: Cai
authors.forename: Xue-Gang
authors.initials: XG
authors.lastname: Luo
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000502:physiology; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000502:physiology; D001369:Axons / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D042241:Early Diagnosis; D006801:Humans; D009422:Nervous System Diseases / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D058225:Plaque, Amyloid / Q000473:pathology
chemical_list: D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human
keywords: Aging; Alzheimer's disease; anti-amyloid therapy; dementia; dystrophic neurites; neurodegenerative disorders; neuroplasticity; senile plaques; synaptic dysfunction